Chain Mediation Analysis Of The Relationship Between Lung Function And Cognitive Function

Aim: In the middle-aged and older population,aging leads to a gradual decline in the physiological functions of various parts of the body to varying degrees,increasing the immune response of the peripheral nervous system,while enhancing the response of the central nervous system to peripheral inflammatory processes and causing the body to enter a pro-inflammatory state,i.e.,systemic hypo-inflammation state.Among them,age-related cognitive impairment is prevalent in middle-aged and older population.Evidence from a series of previous studies have found the closely association between lung function and cognitive impairment.Currently,there are limited studies on exploring the chain mediating factors between the two.Serum C-reactive protein(CRP)level increased with decreased lung function,which was related to subsequent cognitive impairment.In addition,triglyceride-glucose(TyG)index,a satisfactory measure of metabolic dysfunction,increased with decreased lung function,which was related to subsequent cognitive impairment.Previous studies suggested that serum CRP level may be a predictor of metabolic dysfunction.Accordingly,based on data from an 8-year prospective study data,we assessed the relationship between serum CRP levels and TyG index and to explore the chain-mediated effects of both in the relationship between lung function and cognitive function in middle-aged and older adults aged 50 years and over with a systemic low-grade inflammation state from the English Longitudinal Study of Ageing(ELSA).Methods: The prospective cohort data we used was collected from ELSA 2008-2009,2012-2013 and 2016-2017.ELSA is a large ongoing prospective cohort study of adults aged 50 years and over living in England and was first established in 2002.The first data collection(wave 1)was initiated in 2002,with follow-up every 2 years and health screening through nurse visits every 4 years for medical related data.Data are currently updated to wave 9 of the survey and include demographic,economic,social,psychological,cognitive,health,and biological data.In this study,we used wave 4 as the baseline data(2008-09)for obtaining information on the independent variables(lung function)and confounders,and followed up wave 6 and 8 follow-up surveys to obtain information on mediating variables(serum CRP level and TyG index)and dependent variables(cognitive function),respectively,in order to analyze the chain mediating role of serum CRP level and TyG index in the relationship between lung function and cognitive function in middle-aged and older adults with a systemic low-grade inflammation state.Nurses were rigorously trained to perform lung function tests(including forced expiratory volume in 1s(FEV1)and forced vital capacity(FVC))using a hand-held vitalograph spirometer.Cognitive function was measured using a battery of tests in the main ELSA interview and included two measures in this study: memory(including immediate recall and delayed recall)as assessed by the Word Recall Test and executive function as assessed by the Animal Naming Test.Fasting blood samples were collected by nurses at each nurse visit,which were sent to an external laboratory to measure the levels of certain compounds in the blood,including serum CRP,plasma glucose and serum triglyceride level et al.We used TyG index to measure metabolic dysfunction in the present study and it was calculated as ln [fasting glucose×fasting triglycerides/2],both measured in milligrams per deciliter.This study used Stata SE 15.0to process the initial data and initially examine the coefficients of each path within the mediation model in the structural equation model(SEM).Step 1: Examine the associations of FEV1 and FVC at baseline with subsequent cognitive function.Step 2:Examine the associations of serum CRP level and TyG index with subsequent cognitive function.Step 3: Examine the associations between lung function(FEV1 and FVC)at baseline and mediated variables(serum CRP level and TyG index)and the association of CRP with TyG index.Model 1 was an unadjusted model and Model 2 was further adjusted for age,sex,educational qualification,current legal marital status,smoking status,alcohol intake,cardiovascular diseases,chronic lung diseases and dementia.This study used Mplus 8.3 for windows to develop SEM to assess the indirect effects of the simple and chain mediation model(Indirect effect 1,indirect effect 2,indirect effect 3,indirect effect comparison and total indirect effect).All mediation models were fully adjusted models.Finally,bootstrapping(5000 replications)was conducted to estimate the bias-corrected 95% confidence intervals of the indirect effects.We also developed a cross-lagged model based on SEM including information on serum CRP level and TyG index from Wave 4,6 and 8 to assess the sequential causality between the two.Results:1.A total of 1742 middle-aged and older adults aged 50 years and over were included in this study at baseline.Among them,slightly more women(57.58%)than men(42.42%)were included.Higher baseline median of serum CRP level was found in female group and higher baseline median of TyG index was found in male group.Additionally,lung function,including FEV1 and FVC,performed better in male group.The scores of memory in female group were higher than that of male group.2.The mediating effect analysis of lung function,serum CRP level and cognitive function showed that serum CRP level significantly mediated the relationships between lung function and recall scores.The mediating effect coefficient of serum CRP level in the relationship between FEV1 and immediate recall was 0.031(95% confidence Interval(CI): 0.005～0.082,P<0.05),explaining a total of 5.28% of total association;the mediating effect coefficient of serum CRP level in the relationship between FEV1 and delayed recall was 0.033(95%CI: 0.003～0.091,P<0.05),explaining a total of 3.46% of total association;the mediating effect coefficient of serum CRP level in the relationship between FVC and immediate recall was 0.028(95%CI: 0.004～0.070,P<0.05),explaining a total of 8.05% of total association;the mediating effect coefficient of serum CRP level in the relationship between FVC and delayed recall was 0.029(95%CI: 0.002～0.075,P<0.05),explaining a total of 4.01% of total association.3.The mediating effect analysis of lung function,TyG index and cognitive function showed that TyG index acted as a mediator of the relationships between lung function and immediate recall and executive function.The mediating effect coefficient of TyG index in the relationship between FEV1 and immediate recall was 0.052(95%CI: 0.016～0.112,P<0.05),explaining a total of 8.86% of total association;the mediating effect coefficient of TyG index in the relationship between FEV1 and executive function was 0.174(95%CI:0.042～0.384,P<0.05),explaining a total of 8.61% of total association;the mediating effect coefficient of TyG index in the relationship between FVC and immediate recall was0.050(95%CI: 0.017～0.097,P<0.05),explaining a total of 14.37% of total association;the mediating effect coefficient of TyG index in the relationship between FVC and executive function was 0.155(95%CI: 0.027～0.326,P<0.05),explaining a total of 7.15%of total association.4.The results of cross-lagged analysis showed that serum CRP level at wave 4 was associated with TyG index at wave 6.After controlling for the effects of all covariates and autoregressive effects,the TyG index at wave 4 did not predict the serum CRP level at wave 6(β = 0.033,P>0.05),whereas the serum CRP level at wave 4 significantly predicted the TyG index at wave 6(β = 0.078,P<0.05).5.The mediating effect analysis of serum CRP level between lung function and subsequent TyG index showed that serum CRP level mediated the association between lung function(FEV1 and FVC)and TyG index.The indirect effect-0.031(95%CI:-0.058～-0.007)explain 15.12% of the total effect of FEV1 and TyG index and the indirect effect-0.027(95%CI:-0.049～-0.007)explain 13.85% of the total effect of FVC and TyG index.6.The mediating effect analysis of TyG index between serum CRP level and subsequent cognitive function showed that TyG index mediated the association between serum CRP level and immediate recall and executive function.The indirect effect-0.013(95%CI:-0.024～-0.004)explain 22.03% of the total effect of serum CRP level and immediate recall and the indirect effect-0.052(95%CI:-0.094～-0.016)explain 98.11% of the total effect of serum CRP level and executive function.7.The chain mediated effect analysis of lung function,serum CRP level,TyG index and immediate recall revealed that serum CRP level and TyG index mediated the relationship between lung function(FEV1 and FVC)and immediate recall.FEV1(mediated effect percentage: 1.19%)and FVC(mediated effect percentage: 1.72%)may partially influence immediate recall through the chain mediated effect of serum CRP level and TyG index.Conclusion: In a nationally representative cohort of middle-aged and older England adults aged 50 years and over,serum CRP level may significantly predict the subsequent TyG index.Moreover,serum CRP level and TyG index play a chain mediating role in the relationship between lung function at baseline and subsequent cognitive function in a systemic low-grade inflammation state.